Long QT syndrome (LQTS) genetic test reports commonly exclude potentially pro-arrhythmic common variants such as p.Asp85Asn-KCNE1. To determine if a discernible phenotype is associated with p.Asp85Asn-KCNE1 and if relatively common KCNE1 variants underlie transient QT prolongation pedigrees with negative commercial LQTS genetic tests. Retrospective review was used to compare demographics, symptomatology, and QT parameters of individuals with p.Asp85Asn-KCNE1 in the absence of other rare/ultra-rare variants in LQTS-susceptibility genes and those who underwent comprehensive LQTS genetic testing.
Compared to the Genome Aggregation Database, p.Asp85Asn-KCNE1 was more prevalent in individuals undergoing LQTS genetic testing [33/1,248 (2.6%) vs. 1,552/126,652 (1.2%); p=0.0001]. In 19/33 (58%), only p.Asp85Asn-KCNE1 was observed. These patients were predominantly female (90% vs 62%; p = 0.02), less likely to experience syncope (0% vs 34%; p = 0.0007), receive β-blockers (53% vs 85%; p = 0.001), or require an ICD (5.3% vs 33%; p = 0.01). However, they exhibited a similar degree of QT prolongation (QTc, 460 ms vs 467 ms; p = NS). Whole exome sequencing of two commercially genotype-negative pedigrees revealed that p.Asp85Asn-KCNE1 and p.Arg36His-KCNE1 traced with a transient QT prolongation phenotype. Functional characterization of p.Arg36His-KCNE1 demonstrated loss-of-function with a 47% reduction in peak IKs current density in the heterozygous state.
We provide further evidence that relatively common variants in KCNE1 may result in a mild QT phenotype designated as "LQT5-Lite" to distinguish such potentially pro-arrhythmic common variants (i.e. functional risk alleles) from rare pathogenic variants that truly confer monogenic disease susceptibility albeit with incomplete penetrance.
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